Boldrini Laura, Giordano Mirella, Niccoli Cristina, Melfi Franca, Lucchi Marco, Mussi Alfredo, Fontanini Gabriella
Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
Cancer Cell Int. 2017 Nov 17;17:105. doi: 10.1186/s12935-017-0474-y. eCollection 2017.
MiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle. Target transcripts for immune checkpoint molecules such as PD-1/PD-L1 and (programmed cell death-1/its ligand and cytotoxic T-lymphocyte antigen 4) have proven to be beneficial against several solid tumors, including lung adenocarcinoma.
Simultaneous quantification of the expression level of miR-33a and -, - and mRNAs with NanoString technology was performed in 88 lung adenocarcinoma specimens. A cohort of 323 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database was further analyzed, in order to test our hypothesis. Potential interference of -- and gene expression by miR-33a was predicted using the microRNA target prediction program
High miR-33a expression was significantly associated with younger (p = 0.005), female (p = 0.04), patients with low grade (p < 0.0001), early stage (p = 0.03) tumors, and better survival. The hypothesis of the involvement of miR-33a in PD-1/PD-L1/CTLA4 mechanisms was corroborated by the finding of putative miR-33a binding sites in all three genes using the method. We found an inverse correlation between miR-33a and - levels (p = 0.01), as well as for - (p = 0.01) and (p = 0.03) expression, and a significant better prognosis for patients with high miR-33a/low -. TCGA database analysis confirmed that miR-33a high levels were associated with low PD-1 expression and with longer survival on a larger population.
Our study emphasizes the notion of a potential value of miR-33a as a favorable prognostic marker through - regulation.
微小RNA（miRNA）在细胞周期中作为癌基因或肿瘤抑制因子发挥着至关重要的作用。免疫检查点分子如程序性死亡受体1（PD-1）/程序性死亡配体1（PD-L1）以及细胞毒性T淋巴细胞相关抗原4（CTLA4）的靶转录本已被证明对包括肺腺癌在内的多种实体瘤有益。
采用NanoString技术对88例肺腺癌标本中miR-33a以及PD-1、PD-L1和CTLA4 mRNA的表达水平进行同步定量分析。为验证我们的假设，对来自癌症基因组图谱（TCGA）数据库的323例肺腺癌患者队列进行了进一步分析。使用微小RNA靶标预测程序预测miR-33a对PD-1、PD-L1和CTLA4基因表达的潜在干扰。
miR-33a高表达与患者年龄较轻（p = 0.005）、女性（p = 0.04）、肿瘤分级较低（p < 0.0001）、分期较早（p = 0.03）以及更好的生存率显著相关。通过使用该方法在所有三个基因中发现推定的miR-33a结合位点，证实了miR-33a参与PD-1/PD-L1/CTLA4机制的假设。我们发现miR-33a与PD-1水平之间呈负相关（p = 0.01），与PD-L1（p = 0.01）和CTLA4（p = 0.03）表达也呈负相关，且miR-33a高表达/PD-1低表达的患者预后明显更好。TCGA数据库分析证实，在更大的人群中，miR-33a高水平与PD-1低表达以及更长的生存期相关。
我们的研究强调了miR-33a通过调节PD-1作为有利预后标志物的潜在价值这一概念。
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